The major news in this article is how much criminal
settlements and fines against major drug companies have gone up in recent
years, to the extent that states going after drug firms for criminal behavior
(usually overpricing) are almost assured of eventually recouping all of the
costs of the investigation.

A statistic that I have had trouble tracking down in many
instances when I’ve blogged about these big settlements is just what proportion
of drug revenues the company had to pay in fines, so that from the company’s
point of view, there is simply no financial incentive not routinely to skate as close to
the legal thin ice as you can. Parent, in reviewing the total of
$29.38B paid in fines by the “worst offender” major drug firms between 1991 and
2012, helps us out with this fact:

“Although some of these settlement amounts seem astronomical, many drug
companies may consider the settlements a cost of doing business; the total
amount paid in fraud cases by pharmaceutical companies over the past 20 years
represents just two-thirds of the profits made by the 10 largest drug companies
in 2010 alone.”

Public Citizen has added its voice to those calling for
criminal prosecution of responsible company execs, as one of the only ways of
reining in this persistent corruption. (See our earlier post for why misdemeanor
charges against company execs might actually work better for this purpose than
felony charges:

--features an all-star cast of authors, all of whom we’ve
had occasion to praise in earlier posts: Jeanne Lenzer, Jerome Hoffman, Curt
Furberg, and John Ioannidis.

The gang tells us that it would be really nice if the
medical profession would police the guideline-writing process so that
practitioners could be sure that any published guideline was a high-quality
review of solid evidence and as free as possible from distorting biases. This
is what the Institute of Medicine and others have called for, and so far we’ve
done a rotten job of responding. So the burden is on the docs to be critical
readers of guidelines, and editors of journal to be pickier about which ones
they publish and how much disclosure to demand.

The authors then address the counter-attack we’ve considered
here in the past, that financial conflicts are not really important because
they are just another form of bias, and bias is everywhere and cannot be
eliminated from science. Their reply to this assertion is two-fold. First, they
note that other forms of bias tend to be multidirectional; some docs for
instance are biased in favor of surgery for a condition while others are biased
in favor of drug therapy, and so forth. But when there’s money in play, the
bias tends to be unidirectional; all the bias tends to line up on the side that
has the deep pocket.

Their second reply is a version of something I wrote in an
earlier post:

As an individual academic-medicine investigator, I may have a strongly
held belief that the earth is flat. This gives me a strong and pervasive bias.
When I do a study, I will selectively seek out evidence showing that the earth
is flat and tend to dismiss data showing that it isn't. Given a choice of
things to study, my interests will gravitate toward flat-earth issues. My
published papers, if the editors allow them to get through, will contain a
variety of statements tending in a flat-earth direction. And so on.

There are also many things that won't happen. I cannot assure anyone will give
me funding for flat-earth research. I cannot assure that if I get funding, I
won't be the only one; there will be a whole stable of investigators all
studying flat-earth matters. I cannot hire expert science writers to draft all
of my published papers for me to aid them through the editorial review process
and to assure that things about flat-earth are slipped in at every possible
point in the manuscript. I cannot afford to buy tens of thousands of dollars of
reprints of my published articles, making it more likely that journal editors
will be swayed to print them. I cannot afford to hold international
"consensus" conferences at glitzy five-star hotels, in which all the
high rollers in the field are paid big bucks to come and proclaim how
flat-earth thinking is the new best thing in medicine. I cannot donate millions
of dollars to medical specialty societies to assure that when they write their
guidelines on a clinical subject, they'll be sure that paid consultants to
flat-earth thinking dominate the panel and write flat-earth-friendly clinical
practice guidelines, which will then be imposed on practitioners as
"evidence-based." And so on and so on.

There is a big difference, in short, between investigator bias, and
well-funded investigator bias.

The authors of the BMJ
paper then go on to address two other ways that guideline panels can be
inappropriately biased. The first seems initially counterintuitive: filling a guideline
panel with experts in that medical specialty. What could possibly be wrong with
having heart surgeons, for example, write a guideline on heart surgery? The
problem is that there is a peculiar overlap here between
intellectual/professional bias and financial conflict. Heart surgeons as a
group have one way of looking at the world, that tends to involve a scalpel. In
addition to looking at the world that way, they tend to make more money when
more patients seek out their particular ways of solving problems. These
combined intellectual and financial biases are very hard to self-detect and
eliminate.

Who else could be on guideline panels if not content area
experts? This is where we need methodologists who understand study design and
critical appraisal of the medical literature, who often gravitate toward
primary care specialties. An ideal guideline panel would have a majority of
method experts and a minority of content area experts.

The final “red flag” to warn of a badly constituted
guideline panel is panel stacking. This is likely to happen when the chair of
the committee, or many members of the committee, have financial conflicts of
interest, or when the sponsoring organization itself as a huge financial stake
in industry funding. It’s relatively easy for a few key panelists to
cherry-pick other panelists whom they know will agree with their favorite
viewpoint, whether or not those individuals personally have financial
conflicts.

As a final touch, the authors review several recent
guidelines and rate them according to their red-flag list. Not surprisingly,
they rate recent guidelines on cholesterol drugs, treatment of depression, and
heart stents as pretty crummy, while giving the U.S. Preventive Services Task
Force high marks for their stop-using-PSA guidelines.

Background: The European Medicine Agency decided some time
ago that it was high time that the detailed information on the research studies
performed by drug companies to justify the market approval of their products be
made public, and no longer treated as the companies’ proprietary information.
An American firm, AbbVie, which spun off recent from Abbott Labs, has filed
suit to stop this, and has won a preliminary ruling from a European court to
block the release of information.

In his first post, “1 Boring Old Man” embedded a 1-hour
video of a meeting held in Brussels with both industry representatives and
European regulators in attendance, at which one of the panelists was Neal
Parker, an attorney for AbbVie. The blog proceeded to talk about the way
several regulators jumped on Parker for his failure to understand that he was
talking about drug safety and ultimately, people’s lives—and directs the viewer
who doesn’t have a full hour to spare to the part of the video where the
“fireworks” occur. I watched the fireworks but then reeled back a ways to try
to get a sense of Parker’s full presentation.

The lawyer for AbbVie had basically this to say about the
idea that regulators should be transparent with the public about
Pharma-conducted scientific studies:

Drug companies serve an
important public health interest in discovering useful new drugs.

Both “extreme”
positions—that you disclose nothing and that you disclose everything—are
bad; a “balanced” position is good.

Drug companies already
release a ton of information about their scientific research. The question
is how to approach what is now “left over” and not currently disclosed.

Each company is the proper
decision maker as to what to do with its own “left over” information.

AbbVie agrees that some of
this left-over information can have public health value and move science
forward. But (to have “balance”) there has to be reasonable controls
preventing the release of this information to other companies, who would
enjoy a “tremendous competitive advantage” if they had access to it.

One can roughly divide
information into two stacks—there’s the “objective” scientific information
which is routinely released openly; but then there s the “subjective” or
“tactical” information about how the company solves problems related to
the research, how it chooses to take the information forward to the
regulators, etc. It is the latter that ought to be protected as
confidential and as giving other companies unfair advantages if released
to them.

“1 Boring Old Man” draws two conclusions from this
presentation and the ensuing Q&A:

What companies like AbbVie
most want to hide is how much they are doing drug promotion under the
guise of scientific research

People who talk like this
simply cannot be trusted to negotiate in good faith; all they care about
is competitive advantage, and if screwing the public provides competitive
advantage, so be it

There is a third lesson highlighted by a BMJ News account from which the blog
draws some of its information—the drug firms themselves are divided over this
issue with other firms not wanting to go as far as AbbVie. Other firms seem to
have decided that with public trust in them now down in the toilet, the only
“competitive advantage” they might enjoy is tied to coming clean.

So what do I make of all this? Well, I agree at least in
part with our fellow blogger, but I would add a further lesson.

First, I agree that when a guy starts a discussion by
announcing that if I disagree with the position that his company takes, then I
am opposed to both the public health and to “balance,” I would want to
grab for my wallet and head for the door. That guy is just way too slippery for
me to spend time with. So yes, whether such people could ever negotiate in good
faith is a serious question.

But there is another issue here as well. I want to give Neal
Parker just a little more credit than others apparently were. For all his
slipperiness, he had decided that there were a couple of things at
stake—preserving the public health and advancing science on the one hand;
preserving his company’s competitive advantage on the other. In his own head he
thought he had a formula for “balancing” these two goals. But what I think he
proved is that the people in the audience who reacted with shocked disbelief to
some of what he said, and Parker himself, were bound to misunderstand each
other because they were speaking different languages. If you spoke Parker-ese,
or Pharma-ese, then everything he said was perfectly logical and indeed
irrefutable. Which shows to me one more reason why we must find a way to detach
the scientific research enterprise from Pharma funding (as I argued in HOOKED).
There is no way we can square the true goals of science and the public health
with the clearly commercial agenda of the drug industry.

Trying to hit the high points, I note that Sismondo is engaged in an ongoing study of KOLs and their influence that includes having attended a number of industry conferences on KOL identification and management, and interviews with a number of highly paid KOLs and Pharma insiders. He agrees with earlier posts here that the drug firms are increasingly outsourcing KOL management to firms specifically devoted to that enterprise. I have previously tended to stress the KOL who's usually a big fish in a small pond, the physician who's supposedly being paid to talk to other docs, but in reality is being paid bribes for her own high rate of prescribing of the company's drug. Sismondo is concerned more about the other end of the spectrum, the big-pond fish who truly can exert influence across large numbers of docs and are being paid especially to do that. The small-pond types typically command $500 to $1000 per lecture, Sismondo tells us, while the big-pond KOLs can draw down $2500.

One interesting and suggestive observation is that as one moves up the food chain to the truly influential docs, the industry treats them more as partners and with kid gloves, because (as one experienced industry consultant told Sismondo): "the number-one requirement specified by KOLs is: 'protect my reputation.' He goes on to reiterate that KOLs desperately want to avoid the 'appearance of...being an industry 'sell-out.'" This seems extremely important because it suggests that the efforts of us pharmascolds over the past decade has actually had an impact. Since KOLs are, indeed, industry sell-outs, this suggests to me at least that a serious campaign within medicine and biomedical science to thus label them publicly could have a significant impact on the general level of professional behavior. On the other hand, Sismondo is skeptical about transparency alone as a vehicle for positive change, and argues that the new U.S. Sunshine Act will have relatively little impact on KOL activity. If anything, the industry is betting on the continued thriving of KOLs; Sismondo notes that currently 15 to 25 percent of total marketing budgets go to speaking events.

I just now suggested that a possible strategy to reduce the number and the influence of KOLs would be to shame them more. Sismondo seems unsure that this would work: "...the medical profession has been corrupted because a small number of companies with well-defined and narrow interests have inordinate influence over how medical knowledge is produced, circulated, and finally used by physicians to make decisions concerning their patients....Most physicians see the companies as playing legitimate roles when the companies promote products in clinics, when they create and distribute medical research, and when they fund and provide continuing medical education." That is, even if KOLs personally wish to avoid looking like sell-outs to industry, Sismondo claims that the larger profession is quite blasé about whether or not these folks have actually sold out. I'm not sure I totally agree with Sismondo on this pessimistic take on general professional values; see for example:http://brodyhooked.blogspot.com/2013/07/a-recent-survey-on-physicians-attitudes.html

OK, so what do we do about all this, if Sismondo is unsure that shaming KOLs gets us any traction? The big-enchilada solution, for Sismondo, is to break up the industry, separating the research-and-development portion of pharmaceuticals from the selling-and-marketing part. One set of firms would discover new drugs, and once those drugs had been shown to meet high standards of efficacy and safety, those firms would auction off licenses to make and sell the drugs to other firms. This would, Sismondo thinks, remove many of the perverse financial incentives that arise from marketing getting mixed up with research.

Sismondo agrees that this grand solution won't happen anytime soon, so his temporary backup plan is: ban physicians speaking on behalf of drug companies. He argues that nothing is served by this and while firms have every right to market, they could just as well have sales reps give the talks. Of course this ban is just as likely to happen anytime soon as the other proposal, unfortunately. But the point for medical ethics and professionalism is that it could effective happen tomorrow--if only physicians would grow an ethical spine and simply refuse to attend company-sponsored talks.

Friday, September 6, 2013

I’m happy to turn the podium over to Professor Marc Rodwin,
who a while back sent me the message below, which I managed to put aside at the
time without posting, and am now making amends. The topic his symposium
addresses—note the free access to the papers—should be of great interest to
readers of this blog:

I thought you and the readers of your blog might be interested in a
forthcoming symposium on Institutional Corruption and Pharmaceutical
Policy that will be published in the forthcoming issue of the Journal
of Law, Medicine & Ethics, 2013: Vol. 14 (3).

Below I list a bit of information about the symposium. I have also
attached a list of the articles with URL links on SSRN which has free
access. Also, these items can also be obtained through the Edmond J.
Safra Center Lab on Institutional Corruption Web page,

The goals of pharmaceutical policy and medical practice are often undermined
due to institutional corruption — that is, widespread or systemic practices,
usually legal, that undermine an institution’s objectives or integrity. The
pharmaceutical industry’s own purposes are often undermined. In addition,
pharmaceutical industry funding of election campaigns and lobbying skews the
legislative process that sets pharmaceutical policy. Moreover, certain
practices have corrupted medical research, the production of medical knowledge,
the practice of medicine, drug safety, and the Food and Drug Administration’s
oversight of pharmaceutical marketing.

I invited a group of scholars to analyze these issues, with each author
taking a different look at the sources of corruption, how it occurs and what is
corrupted. The articles address five topics: (1) systemic problems, (2) medical
research, (3) medical knowledge and practice, (4) marketing, and (5) patient
advocacy organizations.

Tuesday, September 3, 2013

I forget what I was doing back in the late spring when the
US Supreme Court issued a couple of major rulings on issues of interest to this
blog. I did not have time just then to post about these rulings but made a
mental note to get back to them as soon as possible. Right…Anyway, last week’s New England Journal of Medicine has
forced my hand (main article for subscribers only).

In Association for
Molecular Pathology v. Myriad Genetics, Myriad’s claim to have patented the
gene sequence for the BRCA1 and BRCA2 cancer-causing locations, and hence their
exclusive right to offer a genetic test for those conditions, was at issue. The
article mentions one major downside of one company having this exclusive right
to a genetic test—its price. Myriad charges about $4000 and one competitor firm
is promising to market a test for $1200. The article omitted to mention an
issue that is even more serious regarding medical science and practice. Myriad
has been able to sequester data on the effectiveness of its genetic tests as
proprietary information. That means any physician counseling a patient on
whether or not to be tested, and what a test means, is dependent on the company
profiting from the test to say how well its own test works, and that is rather
obviously a bad situation.

Lower courts had thrown out first all, then only some of the
Myriad patents. The Supreme Court basically split the difference. Some patents
involved the actual DNA that makes up the genes. The court said that exists in
nature and you cannot patent that. But some patents involve complementary DNA
which the company manufactures off messenger RNA that is taken from those
genes. That cDNA does not exist in nature, so the court said the company could
patent that. (Plaintiffs had alleged that cDNA is really the same as native DNA
because what matters is the information in it, not its physical form, and that
is the same as the native DNA; the court did not buy that argument.)

Patient advocates such as the ACLU trumpeted the decision as
a big win because it does now open the door to competing gene tests. Let’s take
a step back, akin to the discussion of patents in HOOKED, and see what basic
issues are involved.

First let’s do Patent Law for Dummies. The noise made these
days by corporate apologists about “intellectual property rights” obscures the
basic fact that a patent is a monopoly. The government is supposed to break up
monopolies, not create them. So the whole idea behind patents is that it’s a tradeoff.
The government grants temporary monopoly rights. In exchange it’s supposed to
get useful innovation that’s in the public good. No patents, no firms willing
to invest their cash in bringing new inventions to market, no innovation to
benefit the public. Too many or too burdensome patents, prices go way up,
public interest is harmed, and in extreme cases (like arguably today’s biotech
sector), innovation is actually squelched.

The law says that patents should be granted only if some
basic conditions are met. The Supreme Court in Myriad issued a very narrow ruling. It decided one issue
only—whether naturally occurring things can be subject to patents—and decided
“no,” in keeping with many earlier rulings. The Court refused to review the
Myriad patents on other grounds, such as whether they met the conditions of
being novel, useful, and non-obvious. Those other grounds are important to most
patents relating to Pharma. The argument against the present patent system for
drugs is that firms are allowed to patent all different aspects of a drug, even
those that are non-useful and obvious. This simply puts barriers in the way of
generic competition, and does nothing to spur innovation.

(As I argued in HOOKED, following Marcia Angell, the Patent
Office could squelch these nuisance patents without any need for a court
ruling, simply by enforcing its own rules. Alternatively, the FDA could refuse
to list any such nuisance patents in its reference book that states the
conditions for drug approval and generic equivalence. But both Federal bodies
are more interested in cozying up to industry, apparently.)

The authors of the NEJM
paper provided a bit of good news in that regard—they report that in recent
years the Patent Office had issued many fewer patents for naturally occurring
gene sequences because they had tightened up their criteria and insisted that
biotech companies could not simply patent genes wholesale, they had to make a
plausible case that they knew how to do something useful with the discovery.
(Presumably the Myriad decision will
raise the bar still higher by ruling out all such patents anyway.)

These address events leading up to the passage of the
Bayh-Dole Act of 1980, that opened the floodgates to universities patenting all
manner of scientific discoveries, including those paid for with federal
research dollars. They make a case for not regarding Bayh-Dole as carved in
stone, but as needing review and updating as conditions have changed so much
since its creation.

All that is a lead-in to a new book, Never Let a Serious Crisis Go to Waste, by a professor of economics at Notre Dame, Philip Mirowski (New York: Verso, 2013). Mirowski explains at a much deeper level why it is that critics of the position taken in this blog, and among the community of pharmascolds, insist that conflict of interest really doesn't exist.

First, on nomenclature--while I offer reasons to prefer the term 'economism' on my blog and in my own book, The Golden Calf, Mirowsky follows the practice of most of our colleagues in history and the social sciences in using the term 'neoliberalism.' So rather than get tangled in who calls it what, I will refer to this ideology henceforth as 'E/N'.

E/N starts off with the claim that the supposedly "free" market is the single most important institution in society, so much so that we ought to regard virtually all of human life as one big market and as following the rules of the marketplace. You might think this is just because a market is such a neat place to buy and sell stuff. But Mirowsky shrewdly notes that one of the great founders of E/N, the Austrian economist Friedrich Hayek, had another reason to glorify the market.

Hayek saw the market as the most perfect information processing system available to human society. If he were writing today, Hayek would probably use the metaphor of the computer. The market is a supercomputer that instantly receives input data from billions of sensors, which are the individual "rational agents" as orthodox neoclassical economics conceives of such a thing.

Now, since all of society ideally ought to be governed by the rules of the market, it follows that the only data worth knowing about anything is its current market price. The market price captures precisely the value of that commodity; the very idea that the market might overvalue or undervalue anything simply does not compute within E/N. The supercomputer of the market takes in all the data from all those who might like to sell a commodity--how much of it they have, and what price they are willing to accept for it. It takes in all the data from everyone who might buy that commodity--how badly they want it, what they might be willing to pay for it, what else they might be willing to forgo, or not, to get some of it. And the computer crunches all those numbers each millisecond to come up with the ever-changing fact, the true market value/price of that commodity.

This is E/N's picture of how society ought to run; and from that picture you can see that there are a number of flies in the ointment, called natural scientists. These folks persist in adhering to a hackneyed, obsolete idea-- that there is another source of valid facts that has nothing to do with how the market functions. These scientists actually think they can consult the body of evidence in their own field, and go into the labs and do experiments, and emerge with data that they view as reliable and true about how the world works.

If these scientists were ever to be taken seriously, all hell would break loose. For the proper role of government, according to E/N, is to stand out of the way and allow the unregulated "free" market to run itself. But so long as these scientists tell politicians that they know some facts--such as, that climate change is a real threat to the human future--then these politicians would be tempted to try to regulate the market to bring about the ends that they desire (like reducing carbon pollution). And that would simply never do. As Hayek famously explained, just let the government think it could regulate even one small thing, and we'd all instantly and permanently lose all of our freedoms.

Now, what in heck does all this have to do with conflict of interest? The point is that the entire ethical argument about conflict of interest assumes, well duh, a conflict of interests. Presumably a scientist has an interest (actually a moral duty) to discover and explain the truth according to the best scientific evidence and methods. If the scientist then proceeds to line his pockets with industry money, he acquires a second interest, in making those industry folks happy and telling them what they want to hear--such as their favorite new drug is extremely safe and effective. The conflict between those two interests is what creates the ethical problem.

How does E/N see this situation? E/N cannot fathom the duality of interests. Since the market is the only reliable source of truth about value, then if the scientists accepts payment on the open market for his opinions, the market value of those opinions, not some silly body of scientific evidence, is what determines their truth. So the scientist creates no conflict of interest by becoming a corporate shill.

Mirowski looks at his fellow academics and notes spectrum of opinion on conflicts of interest. At one extreme end he places the biomedical folks. They have gotten their knickers more in a knot than anyone else over conflicts in their field, and have created this new cottage industry of COI guidelines and rules. Maybe that has something to do with the idea that some of them actually care about whether patients live or die after being given the newest drugs and devices.

At the far other end of the spectrum are the economists. As Mirowski characterizes the field of orthodox neoclassical economics (which has both taken over virtually all university departments of economics, and has also been fully captured by the E/N ideology, to hear his account of it), the typical econ professor takes a ton of money from various corporations, especially banks and financial firms, believes that nonetheless he's a completely neutral arbiter of fact, and discloses none of those financial involvements in his journal articles and other scholarly work. Plaintive calls among a few disgruntled folk after the start of the recent great recession, that the field of economics needed a code of ethics, were ignored.

When we understand what E/N teaches, we can see why the economists have figured out exactly what conflict of interest is all about, and why from their point of view the biomedical scientists are clueless. And that further explains why those within the biomedical community, who have been most sneering and dismissive of conflict of interest as an ethical concern, seem to be among those most committed to the E/N ideology.